<br/>This presentation will provide an overview of a program in our group that utilizes enzymes to provide real-time readout on catalytic efficiency of a set of reactions being screened in parallel. In its current configuration, the In Situ Enzymatic Screening (ISES) method is run in a biphasic configuration whereby the organic reaction takes place in an organic solvent layer, with product or byproduct diffusing to an adjacent buffered, aqueous enzymatic ‘reporting layer.’ The reaction being screened must be compatible with low concentrations of diffusing water, with H<sub>2</sub>O-levels depending upon the choice of organic solvent. Reactions that are promoted by mixed aqueous solvents or that utilize water as a reactant are especially well suited for this screen. To the contrary, as will be shown, the method is compatible with highly air-sensitive reactions, such as those involving a Ni(0)-catalyst outfitted with electron-rich ligands. As will be discussed in this talk, the ISES method has been run in a range of multi-well/multi-cuvette formats and with a variety of ‘reporting enzymes’ allowing the experimentalist to explore reactivity across a notable range of reaction manifolds. Among the transformations that have been investigated by ISES are included: (a) intramolecular allylic amination chemistry, leading to the discovery of the first-ever asymmetric, Ni(0)-mediated allylic amination reaction; (b) (pseudo)halometallation-carbocyclization transformations leading to exomethylene lactone natural product cores and to DOS-(diversity-oriented synthesis) libraries featuring heterocycles bearing an interesting vinyl thiocyanate appendage and (c) the hydrolytic kinetic resolution of epoxides, for which promising new non-C2-symmetric chiral salen ligands have been identified for highly efficient kinetic resolution, particularly where the chiral salen scaffold is matched with the epoxide substrate. Advances in the ISES platform to diversify the types of reactions to be screened will be discussed.

Development and deployment of the in situ enzymatic screening (ISES) method for reaction discovery and catalyst optimization

ACS Spring 2022

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